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J Immunol. 2016 Mar 1;196(5):2205-2218. doi: 10.4049/jimmunol.1502366. Epub 2016 Jan 25.

Extensive CD4 and CD8 T Cell Cross-Reactivity between Alphaherpesviruses.

Author information

1
Department of Medicine, University of Washington, Seattle, USA.
2
Department of Global Health, University of Washington, Seattle, USA.
3
Max von Pettenkofer-Institute, Munich, Germany.
4
Division of Pathway Medicine, University of Edinburgh, United Kingdom.
5
Laboratory of Experimental Immunology, University of Copenhagen, Copenhagen, Denmark.
6
Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia.
7
Department of Medicine, Vanderbilt University School of Medicine, Nashville, USA.
8
Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, USA.
9
Department of Laboratory Medicine, University of Washington, Seattle, USA.
10
Department of Epidemiology, University of Washington, Seattle, USA.
11
Benaroya Research Institute, Seattle, USA.
#
Contributed equally

Abstract

The Alphaherpesvirinae subfamily includes HSV types 1 and 2 and the sequence-divergent pathogen varicella zoster virus (VZV). T cells, controlled by TCR and HLA molecules that tolerate limited epitope amino acid variation, might cross-react between these microbes. We show that memory PBMC expansion with either HSV or VZV enriches for CD4 T cell lines that recognize the other agent at the whole-virus, protein, and peptide levels, consistent with bidirectional cross-reactivity. HSV-specific CD4 T cells recovered from HSV-seronegative persons can be explained, in part, by such VZV cross-reactivity. HSV-1-reactive CD8 T cells also cross-react with VZV-infected cells, full-length VZV proteins, and VZV peptides, as well as kill VZV-infected dermal fibroblasts. Mono- and cross-reactive CD8 T cells use distinct TCRB CDR3 sequences. Cross-reactivity to VZV is reconstituted by cloning and expressing TCRA/TCRB receptors from T cells that are initially isolated using HSV reagents. Overall, we define 13 novel CD4 and CD8 HSV-VZV cross-reactive epitopes and strongly imply additional cross-reactive peptide sets. Viral proteins can harbor both CD4 and CD8 HSV/VZV cross-reactive epitopes. Quantitative estimates of HSV/VZV cross-reactivity for both CD4 and CD8 T cells vary from 10 to 50%. Based on these findings, we hypothesize that host herpesvirus immune history may influence the pathogenesis and clinical outcome of subsequent infections or vaccinations for related pathogens and that cross-reactive epitopes and TCRs may be useful for multi-alphaherpesvirus vaccine design and adoptive cellular therapy.

PMID:
26810224
PMCID:
PMC4761520
[Available on 2017-03-01]
DOI:
10.4049/jimmunol.1502366
[Indexed for MEDLINE]
Free PMC Article

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